In principle, animals would be more fit if parents informed their offspring of the environmental conditions they experienced before the conception of their young. Although inheritance of DNA sequence is largely unaffected by the environment, some epigenetic information can be inherited through the mammalian germ line and may therefore carry environmental information between generations. Epidemiological evidence in humans suggests that poor parental diets can predispose their offspring to cardiovascular disease. We sought to test the hypothesis that epigenetic information transferred between generations can provide offspring with molecular knowledge of the environmental conditions experienced by their parents. To search for transgenerational epigenetic inheritance, we therefore carried out a screen for genes in mice that respond to paternal diet. Our preliminary data demonstrate that the expression of genes involved in lipid biosynthesis and cell proliferation increased dramatically, relative to a cohort of control offspring, when their fathers were fed a low-protein diet. Here, we propose to pursue a comprehensive investigation of the mechanisms of transgenerational control of gene expression in mammals. We will further explore the ability of diet to affect offspring's phenotype, and we will determine whether transgenerational information is carried by sperm, seminal fluid, or some other information carrier. Together, these experiments constitute an extensive characterization of a novel pathway linking diet to phenotype across generations. These results will have important implications for human cardiovascular disease, cancer, and more broadly for the epidemiology of complex diseases.